3-O-Sulfation induces sequence-specific compact topologies in heparan sulfate that encode a dynamic sulfation code

Heparan sulfate (HS) is arguably the most diverse linear biopolymer that is known to modulate hundreds of proteins. Whereas the configurational and conformational diversity of HS is well established in terms of varying sulfation patterns and iduronic acid (IdoA) puckers, a linear helical topology resembling a cylindrical rod is the only topology thought to be occupied by the biopolymer. We reasoned that 3-O-sulfation, a rare modification in natural HS, may induce novel topologies that contribute to selective recognition of proteins. In this work, we studied a library of 24 distinct HS hexasaccharides using molecular dynamics (MD). We discovered novel compact (C) topologies that are populated significantly by a unique group of 3-O-sulfated sequences containing IdoA residues. 3-O-sulfated sequences containing glucuronic acid (GlcA) residue and sequences devoid of 3-O-sulfate groups did not exhibit high levels of the C topology and primarily exhibited only the canonical linear (L) form. The C topology arises under dynamical conditions due to rotation around an IdoA → GlcN glycosidic linkage, especially in psi (Ψ) torsion. At an atomistic level, the L → C transformation is a multi-factorial phenomenon engineered to reduce like-charge repulsion, release one or more HS-bound water molecules, and organize a bi-dentate "IdoA-cation-IdoA" interaction. These forces also drive an L → C transformation in a 3-O-sulfated octasaccharide, which has shown evidence of the unique C topology in the co-crystallized state. The 3-O-sulfate-based generation of unique, sequence-specific, compact topologies indicate that natural HS encodes a dynamic sulfation code that could be exploited for selective recognition of target proteins.